Infection by pandemic strains of influenza A virus, as well as the currently circulating H5N1 avian strains, results in a high rate of lethality, primarily due to the excessive accumulation of proinflammatory cytokines/chemokines that precedes cellular infiltration. In order to combat the excessive inflammation associated with infection, a thorough understanding of the mechanisms underlying mononuclear cell trafficking and dendritic cell biology within the lung is essential. This proposal will test the hypothesis that altered mononuclear cell trafficking and/or dysregulation of dendritic cells within the lung contribute to the high-pathology resulting from infection with lethal H5N1 strains of influenza A virus. In this study, the kinetics, phenotype, and differentiation of mononuclear cell trafficking from the bone marrow to the lung will be characterized following infection. These data will be used to determine critical differences in the course of innate activation between lethal and sublethal infections. Using a knockout mouse (CCR2-/-) deficient in dendritic cell accumulation in the lung, the specific contribution of dendritic cells to both host pathology and viral clearance will be examined. Specifically, these experiments will focus on direct viral clearance, killing of virus-infected cells, and antigen presentation at the site of infection. The knowledge gained by these experiments will lay the groundwork necessary for development of targeted therapies to reduce the excessive inflammation that contributes to increased host pathology and often death, without compromising the immune mechanisms required for viral clearance. Furthermore, the mechanisms involved in mononuclear cell trafficking from the bone marrow are not intrinsic to only influenza infection. The information gained from these experiments may also provide insight into infection by other pathogens, anti- cancer immunity, as well as auto-immune disorders.